Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

The comparative cost-effectiveness of an equity-focused approach to child survival, health, and nutrition: a modelling approach.

Progress on child mortality and undernutrition has seen widening inequities and a concentration of child deaths and undernutrition in the most deprived communities, threatening the achievement of the Millennium Development Goals. Conversely, a series of recent process and technological innovations have provided effective and efficient options to reach the most deprived populations. These trends raise the possibility that the perceived trade-off between equity and efficiency no longer applies for child health--that prioritising services for the poorest and most marginalised is now more effective and cost effective than mainstream approaches. We tested this hypothesis with a mathematical-modelling approach by comparing the cost-effectiveness in terms of child deaths and stunting events averted between two approaches (from 2011-15 in 14 countries and one province): an equity-focused approach that prioritises the most deprived communities, and a mainstream approach that is representative of current strategies. We combined some existing models, notably the Marginal Budgeting for Bottlenecks Toolkit and the Lives Saved Tool, to do our analysis. We showed that, with the same level of investment, disproportionately higher effects are possible by prioritising the poorest and most marginalised populations, for averting both child mortality and stunting. Our results suggest that an equity-focused approach could result in sharper decreases in child mortality and stunting and higher cost-effectiveness than mainstream approaches, while reducing inequities in effective intervention coverage, health outcomes, and out-of-pocket spending between the most and least deprived groups and geographic areas within countries. Our findings should be interpreted with caution due to uncertainties around some of the model parameters and baseline data. Further research is needed to address some of these gaps in the evidence base. Strategies for improving child nutrition and survival, however, should account for an increasing prioritisation of the most deprived communities and the increased use of community-based interventions.

Atherogenic Dyslipidemia in Latin America: Prevalence, causes and treatment: Expert's position paper made by The Latin American Academy for the Study of Lipids (ALALIP) Endorsed by the Inter-American Society of Cardiology (IASC), the South American Society of Cardiology (SSC), the Pan-American College of Endothelium (PACE), and the International Atherosclerosis Society (IAS).

This is an executive summary made by a group of experts named Latin American Academy for the study of Lipids (ALALIP). In the current clinical guidelines, atherogenic dyslipidemia (AD) is a poorly recognized entity. Due to the frequent lipid alterations associated with AD in Latin America (LA), we organized a group of experts named (ALALIP) to generate a document in order to analyze their prevalence and to offer practical recommendations. METHODOLOGY: using the Delphi methodology, we conducted a comprehensive literature review with emphasis on those publications related to LA. Subsequently, we developed key questions for discussion. As a convention, those recommendations that had a 100% of acceptance were considered unanimous, those with >80% were consensual, and those with <80% were in disagreement. RESULTS: a systematic analysis of national health surveys and regional cohort studies showed a consistently high prevalence of the lipid abnormalities that define AD: low levels of high-density lipoprotein cholesterol (HDL-C) range from 34.1% to 53.3% and elevated triglycerides (TG) range from 25.5% to 31.2%. These abnormalities could be related to high consumption of food with a high caloric density, cholesterol and trans fats, a sedentary lifestyle and perhaps epigenetic changes CONCLUSIONS: lipid abnormalities that define AD have a high prevalence in LA. The interaction between an unfavorable lifestyle, inheritance and epigenetic changes is probably their cause. It is important to design a global study of risk factors in LA to know its true prevalence in the region, its consequences and to derive from its treatment strategies.

Atherogenic dyslipidemia in Latin America: prevalence, causes and treatment. Consensus / Dislipidemia aterogénica en Latinoamérica: prevalencia, causas y tratamiento. Un consenso

Abstract: Atherogenic dyslipidemia (DA) is a poorly recognized entity in the current clinical practice guidelines. Due to the frequent lipid alterations associated with this metabolic abnormality in Latin America (LA), we organized a group of experts that has adopted the name of Latin American Association for the study of Lipids (ALALIP), to generate a document for analyzing in LA the prevalence of the lipid profile related to this condition, and to offer practical recommendations for its optimal diagnosis and treatment. Methodology: It was is selected a group of regional experts and, using a modified Delphi methodology, we conducted a comprehensive literature review, with emphasis on studies or reviews that had implications for LA. Subsequently developed a series of key questions about the epidemiology, pathophysiology, diagnosis, and treatment of the AD to be discussed by the group of experts. As a convention those recommendations that had 100% acceptance was consider unanimous; those with at least 80% as for consensus, and of disagreement, those with less than 80%. Results: Although there is no a global study on risk factors that has been made on the basis of a representative sample of the entire population of LA, the systematic analysis of the national health surveys and regional cohort studies based on local population sampling shows a consistent evidence of the high prevalence of the lipid abnormalities that define the AD. The prevalence of low levels of high density lipoprotein cholesterol (HDL-C) ranges from 34.1% (CESCAS I study) to 53.3% (LASO study), with different frequencies between men and women and the selected cut-off point. The prevalence of elevated triglycerides (TRG) varies from 25.5% (LASO study) to 31.2% (National Health Survey of Chile) being always more prevalent in men than in women. Only two studies report the prevalence of AD in LA: the National Health Survey of Mexico 2006 with an 18.3%, and a Venezuelan study that estimates the weighted prevalence of AD in 24.7%. There are multiple causes for these findings: an inadequate nutrition-characterized for high consumption of foods with a high caloric density and a high intake of cholesterol and trans fats-, a sedentary lifestyle, a high prevalence of obesity in the region, and possibly epigenetic changes that make our population more susceptible for having this abnormal lipid profile. Conclusions: Lipid abnormalities that define AD have a high prevalence in LA; the interaction between the style of living, the inheritance, and epigenetic changes possibly are its cause. Since they are considered as an important cause of residual cardiovascular risk, they must be diagnosed and treated actively as a secondary target after reaching the goal for low density lipoprotein-cholesterol (LDL-C). It is important to design a global study of risk factors in our region to let us know the true prevalence of AD and its causes, and to help us in the design of public policies adapted to our reality in a population and individual scale.

Resumen: La dislipidemia aterogénica (DA) es una entidad poco reconocida en las guías de práctica clínica actuales. Debido a las frecuentes alteraciones lipídicas asociadas a esta anomalía metabólica en América Latina (AL), hemos organizado un grupo de expertos que ha adoptado el nombre de Asociación Latinoamericana para el Estudio de Lípidos (ALALIP), para generar un documento en el que se analice la prevalencia en AL del perfil lipídico relacionado con esta afección y ofrecer recomendaciones prácticas para su óptimo diagnóstico y tratamiento. Metodología: Se seleccionó un grupo de expertos regionales y, utilizando una metodología Delphi modificada, se realizó una revisión bibliográfica exhaustiva, con énfasis en estudios o revisiones que tuvieran implicaciones para AL. Posteriormente se desarrolló una serie de preguntas clave sobre la epidemiología, la fisiopatología, el diagnóstico y el tratamiento de la DA, que fueron discutidas por el grupo de expertos. Como convención, las recomendaciones que tuvieron un 100% de aceptación fueron consideradas unánimes; aquellas con al menos el 80% como para el consenso, y de desacuerdo, aquellas con menos del 80%. Resultados: Aunque no existe un estudio global sobre los factores de riesgo que se haya realizado sobre la base de una muestra representativa de toda la población de AL, el análisis sistemático de las encuestas nacionales de salud y los estudios de cohortes regionales evidencian la alta prevalencia de las anormalidades lipídicas que definen la DA. La prevalencia de niveles bajos de colesterol de lipoproteínas de alta densidad (HDL-C) oscila entre el 34.1% (estudio CESCAS I) y el 53.3% (estudio LASO), con diferentes frecuencias entre hombres y mujeres y el punto de corte seleccionado. La prevalencia de triglicéridos elevados (TRG) varía de 25.5% (estudio LASO) a 31.2% (Encuesta Nacional de Salud de Chile) siendo siempre más prevalente en hombres que en mujeres. Sólo dos estudios informan la prevalencia de DA en AL: la Encuesta Nacional de Salud de México 2006 con un 18.3%, y un estudio venezolano que estima la prevalencia ponderada de la DA en 24.7%. Existen múltiples causas para estos hallazgos: una nutrición inadecuada -caracterizada por el alto consumo de alimentos con alta densidad calórica y un alto consumo de colesterol y grasas trans- un estilo de vida sedentario, una alta prevalencia de obesidad en la región y posiblemente cambios epigenéticos que hacen que nuestra población sea más susceptible a tener este perfil lipídico anormal. Conclusiones: Las anomalías lipídicas que definen la DA tienen una alta prevalencia en AL; la interacción entre el estilo de vida, la herencia, y los cambios epigenéticos posiblemente son su causa. Debido a que se consideran una causa importante de riesgo cardiovascular residual, deben ser diagnosticados y tratados activamente como un objetivo secundario después de alcanzar la meta para el colesterol de lipoproteína de baja densidad (LDL-C). Es importante diseñar un estudio global de los factores de riesgo en nuestra región para hacernos conocer la verdadera prevalencia de la DA y sus causas y ayudarnos en el diseño de políticas públicas adaptadas a nuestra realidad en una escala poblacional e individual.

Dislipidemia aterogénica en Latino América: prevalencia, causas y tratamiento / Atherogenic dislipidemia in Latin America: prevalence, causes and treatment

En las guías clínicas actuales, la dislipidemia aterogénica (DA) es una entidad escasamente atendida. Debido a las frecuentes alteraciones en los lípidos asociados a la DA en Latino América (LA), se organizó un grupo de expertos que se ha denominado Academia Latino Americana para el estudio de los Lípidos (ALALIP) para generar un documento con análisis de su prevalencia y ofrecer recomendaciones prácticas. Se utilizó la metodología Delphi modificada, con revisión comprensiva de la literatura con énfasis en aquellas publicaciones con implicaciones para LA. Subsecuentemente, se desarrollaron preguntas claves para ser discutidas. En LA no existe un estudio global sobre los factores de riesgo que representan a la totalidad de la población. El análisis sistemático de las encuestas nacionales de salud y de los estudios sistemáticos de cohorte muestran consistentemente una alta prevalencia de las anormalidades lipídicas que definen la DA. La concentración baja del colesterol unido a las lipoproteínas de alta densidad (C-HDL) varía entre 34,1% a 53,3% y la de triglicéridos (TG) elevados del 25,5% al 31,2%, con mayor prevalencia entre los hombres. Múltiples causas se han reconocidos, como alta ingesta de alimentos de mayor densidad calórica, contenido de colesterol, grasas trans, sedentarismo y cambios epigenéticos. La DA bien puede ser tratada con los cambios terapéuticos del estilo de vida (CTEV) con incremento en la actividad física, ejercicio regular y dieta baja en carbohidratos y alta en ácidos grasos poliinsaturados, tales como los ácidos grasos omega-3 como intervención primaria. De ser necesario, esta estrategia sera suplementada con terapia farmacológica como la monoterapia con estatinas o la combinación de fibratos/ácidos grasos omega-3. Las anormalidades lipídicas que definen la DA tienen una elevada prevalencia en LA; su interacción con un estilo de vida no saludable, herencia y cambios epigenéticos están ligados a sus posibles causas. La DA es una causa importante de riesgo cardiovascular residual (RCVR) que debe ser diagnosticada y tratada. Es importante y necesario diseñar un estudio global de factores de riesgo en LA para conocer la real prevalencia de la DA.

In the current clinical guidelines, atherogenic dyslipidemia (AD) is a poorly recognized entity. Due to the frequent lipid alterations associated with AD in Latin America (LA), we organized a group of experts named Latin American Academy for the study of Lipids (ALALIP), to generate a document for analyzing its prevalence and to offer practical recommendations. Using the Delphi methodology, we conducted a comprehensive literature review, with emphasis on those publications with implications for LA. Subsequently we developed key questions to be discussed. In LA there is no a global study on risk factors that represent the entire population. The systematic analysis of national health surveys and regional cohort studies showed a consistent high prevalence of the lipid abnormalities that define AD. Low high density lipoprotein cholesterol (HDL-C) ranges from 34.1% to 53.3% and elevated triglycerides (TG) from 25.5% to 31.2%, more prevalent in men. There are multiple causes: high consumption of foods with a high caloric density, cholesterol and trans fats, sedentary lifestyle and epigenetic changes. AD must be well treated with therapeutic changes in lifestyle with increased in physical activities, regular exercise and a diet with a low proportion of carbohydrates y rich in poliunsatured fatty acid, such as omega-3 fatty acid as primary intervention. If needed, this strategie must be supplemented with pharmacological therapies such as monotherapy with statins or a combination of fibrates plus omega-3.fatty acid. Lipid abnormalities that define AD have a high prevalence in LA; the interaction between non-healthy lifestyle, inheritance and epigenetic changes, possibly are its cause. AD is an important cause of cardiovascular residual risk (CVRR), that must be diagnosed and treated. It is important and neccesary to design a global study of risk factors in LA to know the true prevalence of AD.

Dislipidemia aterogénica en latino américa: prevalencia, causas y tratamiento / Atherogenic dyslipidemia in Latin America: prevalence, causes and treatment

En las guías clínicas actuales, la dislipidemia aterogénica (DA) es una entidad no muy atendida. Debido a las frecuentes alteraciones en los lípidos asociados a la DA en Latino América (LA). Métodos: organizamos un grupo de expertos denominado Academia Latino Americana para el estudio de los Lípidos (ALALIP) para así generar un documento con análisis de su prevalencia y recomendaciones terapéuticas prácticas. Se utilizó la metodología Delphi modificada, con una revisión integral de la literatura y énfasis en las publicaciones con implicaciones para LA. Subsecuentemente, desarrollamos preguntas claves para ser discutidas. Resultados: En Latinoamérica (LA) no existe un estudio global sobre los factores de riesgo que representan a la totalidad de la población. El análisis sistemático de las encuestas nacionales de salud y de los estudios sistemáticos de cohorte muestran consistentemente una alta prevalencia de las anormalidades lipídicas que definen la DA. La concentración baja del colesterol unido a las lipoproteínas de alta densidad (C-HDL) varía entre 34,1% a 53,3% y la de triglicéridos (TG) elevados del 25,5% al 31,2%, con mayor prevalencia entre los hombres. La DA bien puede ser tratada con los cambios del estilo de vida (CTEV) como ncremento en laactividad física, dieta baja en carbohidratos y alta en ácidos grasos poliinsaturados, tales como los ácidos grasos omega-3 como intervención primaria. De ser necesario, esta estrategia sera suplementada con terapia farmacológica como la monoterapia con estatinas o la combinación de fibratos/ácidos grasos omega-3. Conclusiones: Las anormalidades lipídicas que definen la DA tienen una elevada prevalencia en LA; su interacción con un estilo de vida no saludable, herencia y cambios epigenéticos están ligados a sus posibles causas. La DA es una causa importante de riesgo cardiovascular residual (RCVR) que debe ser diagnosticada y tratada. Es importante y necesario diseñar un estudio global de factores de riesgo en LA para conocer la real prevalencia de la DA(AU)

In the current clinical guidelines, atherogenic Med Interna (Caracas) 2017; 33 (3): 121 - 139 Dislipidemia Aterogénica en Latino América: Prevalencia, causas y tratamiento Carlos I. Ponte-N, Jesús E. Isea-Pérez, Alberto J. Lorenzatti, Patricio López-Jaramillo, Fernando Stuardo Wyss-Q, Xavier Pintó, Fernando Lanas, Josefina Medina, Livia T. Machado-H, Mónica Acevedo, Paola Varleta Alfonso Bryce, Carlos Carrera, Carlos Ernesto Peñaherrera, José Ramón Gómez-M, Alfredo Lozada, Alonso Merchan-V, Daniel Piskorz, Enrique Morales, María Paniagua, Félix Medina-Palomino, Raúl Alejandro Villar-M, Leonardo Cobos, Enrique Gómez-Álvares, Rodrigo Alonso, Juan Colan, Julio Chirinos, Jofre Lara, Vladimir Ullauri, Ildefonso Arocha Documento de la posición de expertos de la Academia Latino Americana para el estudio de los Lípidos (ALALIP) y avalado por la Sociedad Interamericana de Cardiología (SIAC), Sociedad Sur Americana de Cardiología (SSC), el Colegio Panamericano de Endotelio (CPAE) y la Sociedad Internacional de Aterosclerosis (IAS). Publicado en conjunto con las Revistas de la Sociedad Venezolana de Medicina Interna y de la Sociedad Venezolana de ndocrinología y Metabolismo. dyslipidemia (AD) is a poorly recognized entity. Due to the frequent lipid alterations associated with AD in Latin America (LA), we organized a group of experts named Latin American Academy for the study of Lipids (ALALIP), to generate a document to analize it´s prevalence and to offer practical recommendations. Methodology: Using the Delphi methodology, we conducted a comprehensive literature review, with emphasis on those publications with implications for LA. Subsequently we developed key questions to be discussed. Results: In LA There is no a global study on risk factors that represent the entire population. The systematic analysis of national health surveys and regional cohort studies showed a consistent high prevalence of the lipid abnormalities that define AD. Low high density lipoprotein cholesterol (HDL-C) ranges from 34.1% to 53.3% and elevated triglycerides (TG) from 25.5% to 31.2% more prevalent in men. There are multiple causes: high consumption of foods with a high caloric density, cholesterol and trans fats, sedentary lifestyle and epigenetic changes. AD must be well treated with therapeutic changes in lifestyle with increase in physical activities, regular exercise and a diet with a low proportion of carbohydrates and rich in poliunsatured fatty acid, such as omega-3 fatty acids as primary intervention. If needed, this strategy must be supplemented with pharmacological therapies such as monotherapy with statins or a combination of fibrates plus omega-3. fatty acid. conclusions: Lipid abnormalities that define AD have a high prevalence in LA; the interaction between non-healthy lifestyle, inheritance and epigenetic changes, possibly are the cause. AD is an important cause of cardiovascular residual risk (CVRR), that must be diagnosed and treated It is important and necesary to design a global study of risk factors in LA to know the true prevalence of AD(AU)

EFA (9-beta-D-erythrofuranosyladenine) is an effective salvage agent for methylthioadenosine phosphorylase-selective therapy of T-cell acute lymphoblastic leukemia with L-alanosine.

The deficiency of methylthioadenosine phosphorylase (MTAP) in T-cell acute lymphoblastic leukemia (T-ALL) and other cancers, while constitutively expressed in normal cells, allows for selective therapy using L-alanosine, an inhibitor of de novo AMP synthesis. We demonstrate that MTAP- T-ALL cells obtained at relapse are as sensitive to L-alanosine toxicity as diagnosis samples. The therapeutic index of L-alanosine can be increased by the use of a MTAP substrate, which protects MTAP+ normal cells. Since MTAP substrates MTA and 5'deoxyadenosine are prone to toxicities associated with adenosine, we synthesized and evaluated a potentially nontoxic MTAP substrate, 9-beta-D-erythrofuranosyladenine (EFA). The cytotoxicity of EFA to hematopoietic progenitors erythroid burst-forming units (BFU-Es) and granulocyte-macrophage colony-forming units (CFU-GMs) was at least 26- to 41-fold less than that of MTA. In addition, EFA selectively rescued MTAP+ MOLT-4 cells from L-alanosine toxicity at 25 microM with negligible toxicity even at 100 microM. As for MTA, significant, albeit incomplete, rescue was achieved at 12.5 microM, but higher concentrations were toxic. EFA at 20 microM or less rescued primary MTAP+ T-ALL cells and normal lymphocytes from L-alanosine toxicity. Collectively, these data indicate that EFA is an effective agent for salvaging MTAP+ cells from L-alanosine toxicity and is superior to MTA due to lower cytotoxicity.

Aspectos genéticos, clínicos y fisiopatológicos del síndrome metabólico / Genetical, clinical and pathophysiological aspects of the metabolic syndrome

Desde 1988 se describe el síndrome metabólico (SM) como una forma de identificar a las personas con alto riesgo de enfermedad cardiovascular y se propone que la obesidad es indispensable para el diagnóstico del SM La industrialización permitió cambios en el estilo de vida: una disminución del ejercicio físico y el consumo de una dieta alta en calorías, rica en grasa y pobre en fibra dietética. Desde el punto de vista evolutivo el hombre desarrolló un genotipo ahorrador, que asegura los cambios metabólicos necesarios para acumular glucógeno muscular y triacilglicéridos en el tejido adiposo durante los períodos de escasez. Cuando esta carga genética se somete a períodos de abundancia puede provocarse un conjunto de trastornos que favorecen la aparición de enfermedades crónicas no trasmisibles. Así se establecen los criterios para el diagnóstico de SM: Obesidad abdominal, hipertrigliceridemia, disminución plasmática de HDL y aumento de glucemia. En esta revisión se destaca la importancia de la obesidad en la aparición de enfermedad cardiovascular (ECV) y el síndrome de resistencia a la insulina para abordar el SM. Respecto al diagnóstico de SM se discuten los cambios en los puntos de corte para las variables diagnósticas y la posible importancia de esta modificación. Se incluyen comentarios sobre los mecanismos fisiopatológicos propuestos para el desarrollo de este síndrome, y se hace énfasis en la importancia del diagnóstico y estudio del SM como elemento preventivo de ECV.

Anastomosis vasculares "suspendidas" / Suspended vascular anastomosis

Los autores presentan una modificación técnica de las anastomosis vasculares con sutura continua, que utilizan sistemáticamente desde hace varios años. Es posible gracias a la gran facilidad para deslizar las suturas monofilamento sintéticas modernas. Consiste en la realización de la primera mitad de la sutura con los cabos vasculares separados bajo control visual directo de la luz, la íntima y el borde de los mismos; luego en ponerlos en contacto haciendo deslizar el hilo por tracción suave. Permite confeccionar fácil y rápidamente anastomosis vasculares técnicamente correctas en situaciones difíciles tales como vasos de pequeño tamaño, profundos, o que no es posible disecar en extensión suficiente